Synchronization of light flash with the irradiation pulse in proton beam therapy: A case report

Research highlight • The proton beam pulse and the light sensing almost occurred simultaneously.• The time between the proton beam pulse and the light sensing was comparable to the general visual reaction time.• In the latter part of the treatment, the time between proton beam pulse and the light sensing tended to be shorter.


Introduction
Light flash during radiotherapy is experienced by some patients and may be due to Cherenkov light or stimulation of the retina. Cherenkov light is produced when a charged particle travels through a transparent medium at a greater speed than light [1]. Tendler et al. demonstrated projected Cherenkov light in patients' eyes during radiotherapy [2]. However, most previous studies have been based on self-reports of patients, and synchronization between the timing of proton beam delivery and light flash sensing is unclear. Therefore, we investigated the correlation of timing of beam delivery and light flash sensing objectively and quantitatively using a recording device in a patient who received proton beam therapy (PBT) for nasopharyngeal adenoid cystic carcinoma.

Patient and disease course
An 83-year-old man visited our center with a chief complaint of epistaxis. Nasopharyngeal endoscopy revealed a mass in the nasopharynx, and a diagnosis of nasopharyngeal hemangioma was made based on gross findings and magnetic resonance imaging (MRI). The patient was followed up with periodic visits, but after 8 years, the tumor had enlarged and biopsy led to a diagnosis of adenoid cystic carcinoma. The tumor had partially invaded the skull base near the orbit (Fig. 1a,  1b). The patient opted for PBT after a head and neck surgeon determined that surgery would be difficult because the primary lesion was located in the nasopharynx. The patient had no medical history other than sinusitis, and the Karnofsky Performance Status was determined to be 90.
The treatment field included the entire nasopharynx. The clinical target volume (CTV) was set to include the tumor plus 5 mm. Passivescattering PBT was delivered to the target with 2 ports (Fig. 1c, 1d). The retina and optic nerve were partially included in the irradiated area. Proton beam irradiation of 2.5 Gy (relative biological effectiveness, RBE) was administered 5 times a week for a total of 65 Gy (RBE) in 26 fractions. The energy of the proton beams was 200 MeV, which were delivered by the synchrotron every 2 s as a pulse of width 0.3 s. The dose rate was 1.9-3.1 Gy/min. The patient complained of light flash during the first session of PBT and sensed light flash in every treatment for two weeks, so we obtained his consent to participation in the current study.

Recording of light flash sensing
We made a small recorder based on a modified nurse call and asked the patient to push the recorder button when he sensed a light flash, and to release the button when the light flash disappeared. As the patient pushed the button of the recorder, an electrical signal of light flash sensing was sent to the event recorder. Similarly, the proton beam pulse was transferred as an electrical signal to the event recorder, so that each signal was recorded as a separate event (Fig. 2). The recorded events were sent to a PC with time information and analyzed on the PC. These measurements were achieved in 13 of the 26 fractions. The pulse time was defined as the time of proton beam irradiation, the sensing time as the time the patient was pressing the button, and the reaction time as the time between the start of proton beam irradiation and the time the patient started to press the button (Fig. 3a-c).

Results
Of the 430 pulsed proton beams, 426 sensations of light flash were confirmed, giving a sensing rate of 99.1%. The rate at which the button was pressed by the patient without proton beam irradiation  Fig. 4. A reaction time of 0.3 to 0.4 s occurred for 364 cases (86%) and there was a tendency for reaction time to decrease from the beginning to the latter half of each session.

Discussion
Light flashes have been described in irradiation of head and neck tumors, but evidence for this phenomenon is often based on personal statements of patients [3][4][5][6][7][8]. Wilhelm-Buchstab et al. recorded light flash sensing using an event recorder and analyzed the relationship between visual sensation and the treatment beam path [9], with the finding that light flash had the highest probability when the optic chiasm and optic tract were included in the beam path. However, as far as we are aware, a relationship between the timing of a light flash sensation and beam on/off has not been suggested previously. Using a proton beam delivered in a pulsed fashion, we were able to examine the relationship between pulse timing and the duration of light sensing objectively, even though no light or sound is generated within the treatment room. Our results suggested that light flashes were correlated with the pulse of proton beam irradiation.
The median reaction time was 0.35 s, which is the time lag between the start of the proton beam pulse and the patient starting to press the button. Generally, visual reaction time is 0.2-0.4 s and tends to be slower in elderly people [10]. The patient was 83 years old, so this time lag is consistent with the general visual reaction time in elderly people. Repetition of similar stimuli is known to shorten the reaction time [11] and this tendency was also observed in this case. The fact that the reaction time was within the general visual reaction time range and was shortened by repeating the same stimuli supports the idea that proton beam irradiation is perceived through the visual pathway.
Cherenkov light is generally produced less frequently during PBT because the energy of proton beams is too low. The energy required to produce Cherenkov light by the proton beam itself is estimated to be > 482 MeV [12] and the energy of the proton beam is 155-250 MeV at our center, which is far below this threshold. However, some reports have suggested sensing of light flash during PBT for the head or head and neck region [3,4]. Helo et al. suggested that direct stimulation of the retina by treatment beams or secondary electrons may influence light flash [13]. The minimum energy of a proton beam required to generate Cherenkov light via secondary electrons is 120 MeV, which can be achieved with the proton beam at our center. In this case, all beams included visual pathways such as the retina, optic nerve, and chiasma; therefore, it becomes challenging when we attempt to determine if the light flash is caused by direct stimulation or by the influence of secondary electrons. However, the time of generation of secondary electrons is several nanoseconds in PBT [13], and thus, the time lag with beam delivery is almost negligible. Given that the time lag between beam delivery and the light flash sensation in this case matches the general visual reaction time, it suggests that the idea of secondary electrons inducing light flash sensation does not conflict with our findings. Nevertheless, more comprehensive research is required to fully unravel the process underlying this observed phenomenon.
Definitive conclusions cannot be drawn from a single case report, but our finding that light flash coincided with the proton beam pulse is of interest. Use of the same method for more patients receiving PBT with various ports will allow a more detailed analysis of light flash, including the dose threshold and related irradiation sites.

Conclusion
The results of this study show that light flashes during proton beam therapy and the timing of irradiation pulses are synchronized.
Declarations Ethics approval and consent to participate: Informed consent was  obtained from the patient. Consent for publication: The patient consented to publication of this report.
Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions: All authors read and approved the final manuscript.